The type I receptor tyrosine kinase family consists of four closely related receptors: EFGR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER) and ErbB4 (HER4). These are transmembrane glycoprotein receptors which contain an extracellular ligand binding region and, with the exception of erbB3, an intracellular catalytically active tyrosine kinase domain. These receptors transmit extracellular signals through the cytosol to the nucleus. The extracellular signal is transmitted by ligand binding to the homomeric receptor, with the exception of erbB2, of which a high affinity soluble ligand has yet to be identified. After ligand binding the type I receptor tyrosine kinases either homodimerize or heterodimerize with another member of the subfamily of receptors. ErbB2 participates in this process by heteromerization. In fact, it has been shown that erbB2 is the preferred heterodimerization partner (Mehelsohn Oncogene 2000). Dimerization leads to activation by autophosphorylation of the intracellular domain. This autophosphorylation recruits other proteins and leads to a phosphorylation cascade that transmits the signal throughout the cell. The type I receptor tyrosine kinase family signals through the ras/raf/MEK/MAPK pathway as well as the PI3K/Akt pathway. These signaling pathways lead to both cell proliferation and cell survival through inhibition of apoptosis.
Several investigations have demonstrated the role of EGFR and ErbB2 in cancer. Squamous carcinomas of the head and neck, and lung express high levels of EGFR. Also, constitutively active EGFR has been found in gliomas, breast cancer and lung cancer (Salomon et al Crit. Rev Oncol Hematol 1995, 19, 183-232—on order Jun. 4, 2002). ErbB2 overexpression occurs in ˜30% of all breast cancer. It has been also implicated in other human cancers including colon, ovary, bladder, stomach, esophagus, lung, uterus and prostate. ErbB2 overexpression has also been correlated with poor prognosis in human cancer, including metastasis, and early relapse (ref—two Slamon refs from Science and Klapper review).
The type I tyrosine kinase receptor family has been an active area of anti-cancer research. Several inhibitors of the EGFR and the ErbB2 signaling pathway have demonstrated clinical efficacy in cancer treatment. Herceptin, a humanized version of anti-ErbB2 monoclonal antibody, was approved for use in breast cancer in the United States in 1998. Iressa and Tarceva are small molecule inhibitors of EGFR that are expected to be launched in 2002. In addition, several other antibodies and small molecules that target the interruption of the type I tyrosine kinase receptor signaling pathways are in clinical and preclinical development (Ciardiello et al).
Several issued patents and applications have appeared describing quinazoline based type I receptor tyrosine kinase inhibitors, including WO 00/44728, WO 01/98277, WO 98/02438, GB 2 345 486 A, WO 96/33980, and references contained therein, which are incorporated herein by reference.